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Joumal of Neurology, Neurosurgery, and Psychiatry 1994;57 (Supplement): 1 -14
Intravenous immunoglobulin therapy in multiple
sclerosis: progress from remyelination in the
Theiler's virus model to a randomised, doubleblind, placebo-controlled clinical trial
John H Noseworthy, Peter C O'Brien, Baziel G M van Engelen, Moses Rodriguez
Abstract
No treatment has been found which
reverses long-standing neurological dysfunction in patients with multiple sclerosis
(MS). Observations in animal models of
MS show that immunoglobulins directed
against CNS components promote oligodendroglial proliferation and new myelin
synthesis. Preliminary studies in inflammatory-demyelinating diseases of the
human peripheral and central nervous
system suggest that the repeated intravenous administration of polyclonal
human immunoglobulin (IVIg) is sometimes followed by clinical improvement. A
randomised, placebo-controlled, doubleblind, clinical trial was designed to test
the hypothesis that repeated administration of IVIg will result in a meaningfiu
degree of recovery of apparently irreversibly lost neurological function (weakness). A total of 76 patients with MS will
participate in the study. These patients had
developed a fixed, apparently permanent
weakness that had not improved in the
preceding four to 18 months. If effective,
IVIg administration may benefit the large
proportion of patients with MS who have
active disease by enhancing the potential
for myelin repair in the evolution of the
inflammatory-demyelinating lesion.
Mayo Clinic and
Mayo Foundation,
Rochester, Minnesota,
USA
Department of
Neurology*
J H Noseworthy
B G M van Engelen
M Rodriguez
Department of Health
Sciences Research
P C O'Brien
Department of
Immunology
B G M van Engelen
M Rodriguez
Correspondence to:
Dr J H Noseworthy,
Department of Neurology,
Mayo Clinic, 200 First
Street SW, Rochester, MN
55905, USA.
CNS remyelination by oligodendrocytesl-5
and Schwann cells6 7 occurs in multiple sclerosis (MS) lesions. It is not known why remyelination and clinical recovery is incomplete.
Whereas oligodendrocyte proliferation and
remyelination is minimal in the centre of
chronic MS plaques, at the edge of demyelinated plaques, remyelination by oligodendrocytes occurs as documented by abnormally
thin myelin sheaths relative to axon diameter.'
These findings suggest the potential for promotion of myelin repair in the evolution of the
inflammatory-demyelinating lesion in MS.
Much of our experimental work has been
focused on efforts to encourage remyelination
in experimental animal models of MS. This
work has led initially to a pilot clinical trial of
intravenous immunoglobulin (IVIg) in MS
patients and, thereafter, to a randomised,
double-blind, placebo-controlled clinical trial.
Experimental studies
We have used a model induced by Theiler's
murine encephalomyelitis virus (TMEV) to
study the mechanisms of demyelination and
remyelination in the CNS.8 Following intracerebral injection of Daniel's (DA) strain of
TMEV into SJL mice, there is extensive
immune-mediated demyelination with relative
absence of remyelination in the spinal cord.8
The demyelination seen following chronic
TMEV infection is indistinguishable pathologically from MS.910 Recurrent episodes of
demyelination are superimposed on the
chronic progressive disease." Histologically
there is primary demyelination (destruction of
myelin sheaths with axon preservation), and
lymphocytes, plasma cells and macrophages
are intimately involved in the demyelinating
lesion.
The precise mechanisms by which TMEV
induces demyelination is unknown. Because
TMEV injures oligodendrocytes, cytopathological injury to oligodendrocytes may result
in demyelination.12 13 The observation that
nude mice develop demyelination following
TMEV infection indicates that T-cells are not
required for the initiation of demyelination.14
In addition, there is considerable evidence
implicating an immune-mediated mechanism
underlying TMEV-induced demyelination.
The inflammatory infiltrate is closely
associated morphologically with areas of
demyelination.'0 Immunosuppression with
cyclophosphamide, anti-lymphocyte serum,
cyclosporine and monoclonal antibodies
(mAbs) to class II MHC products reduces the
extent of demyelination. 15-18 Both class Irestricted and class II-restricted T-cells
appear to be important in the late phases of
TMEV-induced demyelination. In vivo therapy with mAbs directed against class Irestricted CD8+ T-cells or class II-restricted
CD4+ T-cells suppresses the extent of
demyelination.'9 20
Administration of emulsions of myelin
basic protein plus galactocerebroside and
incomplete Freund's adjuvant may enhance
remyelination in the chronic guinea pig EAE
model."-2' We therefore considered the possibility that differences in remyelination in the
TMEV model may be determined by the
immune response. Immunisation with serum
directed against spinal cord homogenate
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12
Noseworthy, O'Brien, van Engelen, Rodriguez
(anti-SCH serum) induced extensive remyelination in SJL mice chronically infected with
TMEV.24 To determine whether the humoral
immune response was important in controlling remyelination, mice chronically infected
with TMEV were treated for up to nine
months with intraperitoneal injections of antiSCH serum. CNS remyelination was extensive in TMEV-infected SJL mice treated with
anti-SCH sera compared with sera from control groups of mice.25
Our recent studies have shown that IgG
contained in the anti-SCH serum was responsible for this effect.2627 In addition to IgG
directed against SCH, commercially prepared, polyclonal mouse IgG also promotes
extensive remyelination in SJL mice chronically infected with Theiler's virus.
Remyelination was not seen with an IgGI
monoclonal antibody (MOPC 21) or in
borate buffered saline-treated control animals.
The polyclonal mouse IgG used in these
experiments was commercially prepared from
nonsyngeneic donor mice and is analogous to
the human IgG preparation proposed in our
clinical trial.
Conventional wisdom has assumed that
IgG plays a role in the putative immunemediated injury in MS. However, the specificity of the IgG molecules in the
cerebrospinal fluid and in the MS lesion
remains undetermined. The concept that IgG
may promote remyelination is novel and has
received little attention.
Clinical studies
We have recently reported the ultrastructural
features of 11 MS stereotactic brain biopsies
with clinical and radiological correlation.28
Oligodendrocytes were morphologically preserved in early lesions and appeared to
increase in number at the edge of plaques in
areas of remyelination. Our results agree with
those of Prineas et al who has shown extensive
oligodendrocyte regeneration and remyelination in acute and subacute MS lesions.' 3 4 The
oligodendrocytes responsible for this remyelination appear to be previously undifferentiated, immature oligodendrocytes rather than,
surviving, previously differentiated mature
myelin-producing oligodendrocytes.
There is preliminary evidence that IVIg
may reverse neurological dysfunction in
patients with long standing optic neuritis.29 A
recently completed study30 suggests that IVIg
administration may be followed by improved
neurological function in patients with
chronic, steroid-unresponsive optic neuritis.
Improvement was temporally related to the
administration of IVIg and persisted for the
follow up period of 1 2-1 7 years. These findings suggest that exogenously administered
human IgG promotes remyelination in patients
with MS with nonresolving optic neuritis.
Possible mechanisms of action of IVIg
The mechanisms of action of IVIg in the few
diseases for which it has proven efficacy are
only partially understood. These include saturation of Fc receptors on reticuloendothelial
cells (acute autoimmune thrombocytopenic
purpura of childhood"3-32) and B and T cells
resulting in modulation of the immune
response,"-'4 reduced natural killer cell activity (autoimmune idiopathic thrombocytopenic
purpura
and
autoimmune
neutropenia35), and neutralisation of putative
autoantibodies by naturally occurring antiidiotypic antibodies within the IVIg preparation.36 37
The mechanism by which polyclonal IgG
promotes remyelination and glial cell proliferation in the Theiler's virus model is unknown.
As discussed above, it is proposed that there
may be antibodies within the anti-SCH serum
that stimulate progenitor glial cell proliferation following binding to a cell surface receptor
responsible for growth or differentiation.
These mechanisms are known to occur in
other examples of autoimmunity.3842
Mayo clinic randomised trial of IVIg
therapy in multiple sclerosis
We are currently completing an open-label,
pilot study of IVIg in 10 patients with MS
using a protocol identical to the proposed fullscale clinical trial (with the exception of the
placebo-controlled limb). This pilot study has
allowed us to assess the safety of IVIg in this
subset of patients with MS, to assess the adequacy of our proposed adverse effects surveillance mechanisms, and to gain experience
with the treatment and outcome measurement methods to be used in the controlled
trial.
The overall goal of this randomised, double-blind and placebo-controlled clinical trial
is to determine whether IVIg administration is
followed by clinical improvement of apparently irreversibly lost motor function (muscle
strength) in patients with MS. This trial differs from other prospective MS clinical trials
because we are attempting to assess whether
experimental treatment results in clinical
improvement rather than delay or prevention
of further progression.
Inclusion criteria: Patients must have clinically
definite43 or laboratory supported definite
MS44 which has been either relapsing-remitting or relapsing-progressive (secondary progressive) from onset. Patients must be
between the ages of 18 and 60 and have a
fixed, apparently irreversible, motor deficit
("targeted neurological deficit"): weakness of
at least one limb which has been documented
in the Departrnent of Neurology at the Mayo
Clinic to have been present and static for four
and 18 months).
Patients must not have received ACTH,
immunosuppressive therapy, corticosteroids,
or plasma exchange within the preceding
three months. The observed duration of the
fixed neurological motor deficit was chosen to
minimise the likelihood of delayed, spontaneous, unexpected and possibly placeborelated recovery of the 'targeted neurological
deficit'.45
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13
Intravenous immunoglobulin therapy in multiple sclerosis
Exclusion criteria: This includes primary progressive MS, pregnancy,4647 ischaemic heart
disease, cerebrovascular disease, dementia,
antibody deficiency states, sensitivity to IVIg
and albumin, and medical illnesses requiring
IVIg administration.
Protocol schedule: In this trial, 76 patients will
be randomised to receive either IVIg
(Gamimune N, Miles Pharmaceuticals; 5%
solution in 10% maltose) or placebo (0- 1%
human serum albumin in 10% maltose) daily
for five days and thereafter every two weeks
for three months (total: 11 infusions). All
patients will be re-examined at three and six
months. In our efforts to determine whether
long-standing motor dysfunction can be
reversed by this treatment, we will measure
the effect of IVIg on motor function using several techniques.
The primary outcome will be the impact of
IVIg (placebo) on muscle strength as determined by serial quantitative isometric muscle
strength measurements in the limbs affected
by the 'targeted neurological deficit' (for
example, monoparesis/plegia, paraparesis/plegia and hemiparesis/plegia). Specifically, the
examining neurologist will indicate the targeted neurological deficit and corresponding
isometric muscle strength testing sites at the
enrolhnent visit. The test results at each site is
the site specific strength, recorded as the percentage of normal (age and sex match controlled). These values will be averaged over
the targeted sites for computation of the primary endpoint. We will then compute the difference between the six month and baseline
value for each subject. Important secondary
outcome measures will include an analysis of
whether IVIg treatment (placebo) influences
either dexterity and gait (serial videotaped
examinations), spasticity (serial recordings of
muscle tone; Ashworth spastity scale,48 49) and
function (Functional Independence Measure;
Box and Blocks and 9 Hole Peg Tests).
Although patients with tremor or truncal
ataxia will not be excluded from enrollment,
these functions will not be selected for study
as the 'targeted neurological deficit'. All data
will be used in these analyses, with patients
analysed according to the treatment group to
which they were randomised (intent to treat
analysis).
This randomised, controlled trial has
considerable practical relevance to MS. If
improvement is seen, the time course of this
change may provide insight into possible
mechanisms of action of IVIg in MS and
may suggest additional strategies which could
be used to maximise the degree and rate of
response. Additional studies will be necessary
to determine whether similar improvements
in other neurological functions will follow
repeated IVIg administration (for example,
cerebellar and sensory function, vision, bowel
and bladder control, cognition, etc).
Subsequent studies could be designed to
determine whether IVIg administration is
beneficial in the setting of either acute
exacerbations (relapsing-remitting or relapsing-progressive disease) or chronic pro-
gressive disease (primary or secondary progressive MS). This trial may provide the
methodological framework to test other
treatment approaches to promote CNS
remyelination.
The studies were
supported by grants from the National
Multiple Sclerosis Society (RG2520-Al, RG 1878-B2 and RG
2174-A3), and the National Institutes of Health (ROI
NS31506-01 Al and RO1-NS24180-06). We thank Miles
Phsrmaceuticals Inc for providing the Gamimune N and
placebo preparations, Diane Sneve, Cathy Hunt and Jennifer
Weis for their nursing expertise and Marian Bortolon for secretarial help.
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Downloaded from http://jnnp.bmj.com/ on June 14, 2017 - Published by group.bmj.com
Intravenous immunoglobulin therapy in
multiple sclerosis: progress from
remyelination in the Theiler's virus model to a
randomised, double-blind, placebo-controlled
clinical trial.
J H Noseworthy, P C O'Brien, B G van Engelen and M Rodriguez
J Neurol Neurosurg Psychiatry 1994 57: 11-14
doi: 10.1136/jnnp.57.Suppl.11
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